tbuckley/cabot-search huggingface dataset:
Young Adult Physical Activity Trajectories and Midlife Nonalcoholic Fatty Liver Disease
Authors: Junia N. de Brito, Daniel J. McDonough, Mahesh Mathew, Lisa B. VanWagner, Pamela J. Schreiner, Kelley Pettee Gabriel, David R. Jacobs, James G. Terry, John Jeffrey Carr, Mark A. Pereira
Journal: JAMA Network Open (2023)

Physical activity (PA) is recommended for preventing and treating nonalcoholic fatty liver disease (NAFLD). Yet, how long-term patterns of intensity-based physical activity, including moderate-intensity PA (MPA) and vigorous-intensity PA (VPA), might affect the prevalence of NAFLD in middle age remains unclear.
An Ultraswelling Microneedle Device for Facile and Efficient Drug Loading and Transdermal Delivery
Authors: Zhiming Li, Puxuan Zhao, Zhixin Ling, Yanting Zheng, Fengli Qu, Hao Chang
Journal: Advanced Healthcare Materials (2023)

Abstract The advancement and extensive demand for transdermal therapies can benefit from a safe, and efficient and user‐friendly transdermal technology with broad applicability in delivering various hydrophilic drugs. Here the design and proof of concept applications of an ultraswelling microneedle device that enables the facile and efficient loading and transdermal delivery of hydrophilic drugs with different molecular weights is reported. The device consists of a super‐hydrophilic hydrogel microneedle array and a resin base substrate. Using a special micromolding technique that involves hydrated crosslinking and cryogenic‐demolding, the microneedle part displays a rapid swelling ratio of ≈3800%, enabling the loading of drugs up to 500 kDa in molecular weight. The drug loading process using the device just involves incubating the microneedle part in a drug solution for 1 min, followed by 15 min of drying. The microneedles can easily penetrate the skin under press and detach from the base substrate under shear, thereby releasing the payload. Administration of desired therapeutic agents using the device outperformed conventional administration methods in mitigating psoriasis and eliciting immunity. This biocompatible device, capable of withstanding ethylene oxide sterilization, can enhance the efficacy and accessibility of transdermal therapies in research institutes, hospitals, and even home settings
Electroactive Polymers for On‐Demand Drug Release
Authors: Manal E. Alkahtani, Moe Elbadawi, Christopher A. R. Chapman, Rylie A. Green, Simon Gaisford, Mine Orlu, Abdul W. Basit
Journal: Advanced Healthcare Materials (2023)

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.
Visualisation of drug distribution in skin using correlative optical spectroscopy and mass spectrometry imaging
Authors: Natalie A. Belsey, Alex Dexter, Jean-Luc Vorng, Dimitrios Tsikritsis, Chelsea J. Nikula, Teresa Murta, Maria-Vitalia Tiddia, Junting Zhang, Elzbieta Gurdak, Gustavo F. Trindade, Ian S. Gilmore, Leanne Page, Clive S. Roper, Richard H. Guy, Mila Boncheva Bettex
Journal: Journal of Controlled Release (2023)

A correlative methodology for label-free chemical imaging of soft tissue has been developed, combining non-linear optical spectroscopies and mass spectrometry to achieve sub-micron spatial resolution and critically improved drug detection sensitivity. The approach was applied to visualise the kinetics of drug reservoir formation within human skin following in vitro topical treatment with a commercial diclofenac gel. Non-destructive optical spectroscopic techniques, namely stimulated Raman scattering, second harmonic generation and two photon fluorescence microscopies, were used to provide chemical and structural contrast. The same tissue sections were subsequently analysed by secondary ion mass spectrometry, which offered higher sensitivity for diclofenac detection throughout the epidermis and dermis. A method was developed to combine the optical and mass spectrometric datasets using image registration techniques. The label-free, high-resolution visualisation of tissue structure coupled with sensitive chemical detection offers a powerful method for drug biodistribution studies in the skin that impact directly on topical pharmaceutical product development.
Influenza Antiviral Shortages Reported by State and Territorial Public Health Officials, 2022-2023
Authors: Noah Kojima, Lisa Peterson, Regina Hawkins, Meredith Allen, Brendan Flannery, Timothy M. Uyeki
Journal: JAMA (2023)

This study provides survey results from state and territorial public health preparedness directors regarding antiviral shortages during the 2022-2023 respiratory viral season.
Specialty Palliative Care and Symptom Severity and Control in Adolescents and Young Adults With Cancer
Authors: Sumit Gupta, Qing Li, Alisha Kassam, Adam Rapoport, Kimberley Widger, Karine Chalifour, Nancy N. Baxter, Paul C. Nathan, Natalie G. Coburn, Rinku Sutradhar
Journal: JAMA Network Open (2023)

Adolescents and young adults (AYAs) with cancer experience substantial symptom burden. Specialty palliative care (SPC) is recommended but often not involved or involved late.To determine whether patient-reported symptom severity was associated with subsequent SPC involvement and whether SPC was associated with symptom improvement in AYAs with cancer.This cohort study comprised AYAs (aged 15-29 years) with primary cancer diagnosed between January 1, 2010, and June 30, 2018, in Ontario, Canada. Data, including self-reported Edmonton Symptom Assessment System (ESAS) scores, were obtained from health care databases. Specialty palliative care was identified through billing codes and validated algorithms. Final data analysis was performed on April 4, 2023.Associations of ESAS scores with subsequent SPC involvement were determined. A difference-in-differences approach was used for patients who died within 5 years of their cancer diagnosis. Case patients (SPC predeath, index date equals first SPC service) were matched 1:1 to control patients (no SPC at equivalent time before death). The study examined whether the difference between 90-day postindex and preindex mean ESAS scores was itself different between case and control patients.This study included 5435 AYAs with cancer, with a median follow-up of 5.1 (IQR, 2.5-7.9) years for analyses of general palliative care. Their median age at cancer diagnosis was 25 (IQR, 22-27) years, and more than half were male (2809 [51.7%]). For all symptoms, moderate and severe ESAS scores were associated with an increased likelihood of SPC involvement compared with mild scores. The greatest magnitude of association was seen for pain scores (hazard ratio for severe vs mild, 7.7 [95% CI, 5.8-10.2]; P < .001). A total of 721 AYAs (13.3%) died within 5 years of diagnosis, and 612 of these patients (84.9%) had received SPC before death. Among 202 case-control pairs, SPC involvement was associated with improved pain trajectories (mean scores improved from 3.41 to 3.07 in case patients and worsened from 1.86 to 2.16 in control patients; P = .003). Other symptom trajectories were not affected.In this cohort study of AYAs with cancer, those reporting moderate or severe symptoms through a screening program were more likely to subsequently receive SPC. These findings suggest that SPC was associated with a subsequent decrease in pain severity but did not affect other symptoms. New interventions targeting other symptoms during treatment and particularly at the end of life are needed.
Exclusionary School Discipline and School Achievement for Middle and High School Students, by Race and Ethnicity
Authors: Camila Cribb Fabersunne, Seung Yeon Lee, Dannielle McBride, Ali Zahir, Angela Gallegos-Castillo, Kaja Z. LeWinn, Meghan D. Morris
Journal: JAMA Network Open (2023)

There are racial and ethnic inequities in exclusionary school discipline (ESD) (ie, a disciplinary action that removes students from their classroom or school environment, eg, referrals, suspensions, and/or expulsions) practices in the US. Exclusionary school discipline has been associated with negative education, health, and criminal justice outcomes.To investigate whether experiencing an ESD event was associated with decreased grade point average (GPA) and whether minoritized students (eg, Black or Latine [description used in database]) are disproportionately affected compared with White students.In a cohort study using retrospective administrative longitudinal data of children in the 6th to 10th grades (August 18, 2014, to May 26, 2017) in a large, single urban school district in California, linear mixed models were applied to compare the timing of the first exclusionary event and the average change in GPA and evaluate the relative variation among minoritized students experiencing an exclusionary event. Data analysis was conducted from August 18, 2018, to August 21, 2023.Year at which students experienced first ESD events over the study period.The primary outcome of interest was change in average grade point average (GPA); students' GPA averaged across courses was averaged across each year.Of the 16 849 students (8756 [52.0%] male), 21.4% experienced at least 1 ESD event. The mean (SD) age was 14.3 (1.6) years, and 7.5% identified as Black, 25.6% Latine, and 10.0% White. Black and Latine students experienced exclusionary events at nearly 10 and 3 times more than White students (mean [SD]: Black, 6.69 [12.80] events; Latine, 2.01 [6.18] events; White, 0.71 [4.46] events; P < .001). When controlling for gender, maternal educational level, race and ethnicity, and school year, having experienced an ESD event in the first year was associated with an average decrease in GPA by 0.88 (95% CI, -0.91 to -0.84) points compared with no ESD events; experiencing ESD events also had significant differences in the second (-0.63 [95% CI, -0.67 to -0.59]) and third (-0.52 [95% CI, -0.57 to -0.47]) years. Black and Latine race and ethnicity was associated with the greatest decrease in GPA compared with White students (Black, -0.56 [95% CI, -0.61 to -0.51]; Latine, -0.51 [95% CI, -0.54 to -0.47]; P < .001).This study observed racial and ethnic inequities in ESD prevalence and its association with educational attainment. The findings suggest that it may be beneficial for pediatricians and other health care professionals to screen for exclusion, as experiencing ESD events may affect health across the life course. In addition, it may be useful to categorize ESD events as an adverse childhood experience and abolish the practice from schools as a disciplinary measure.
Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma
Authors: Daniel P. Petrylak, Bernhard J. Eigl, Saby George, Elisabeth I. Heath, Sebastien J. Hotte, David D. Chism, Lisle M. Nabell, Joel Picus, Susanna Y. Cheng, Leonard J. Appleman, Guru P. Sonpavde, Alicia K. Morgans, Pourya Pourhosseini, Ruishan Wu, Laura Standley, Ruslan Croitoru, Evan Y. Yu
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody–drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. Patients and Methods: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. Results: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. Conclusions: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.
BATF represses BIM to sustain tolerant T cells in the periphery
Authors: Philip J. Titcombe, Milagros Silva Morales, Na Zhang, Daniel L. Mueller
Journal: The Journal of Experimental Medicine (2023)

T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia
Authors: Albert Wiegman, Susanne Greber-Platzer, Shazia Ali, M. Doortje Reijman, Eliot A Brinton, Min-Ji Charng, Shubha Srinivasan, Carissa Baker-Smith, Seth Baum, Julie A. Brothers, Jacob Hartz, Patrick M. Moriarty, Jeanne Mendell, Sébastien Bihorel, Poulabi Banerjee, Richard T. George, Boaz Hirshberg, Robert Pordy
Journal: Circulation (2023)

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C &gt;130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of −48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], –41.3% [9.0%]), non–high-density lipoprotein cholesterol (–48.9% [9.8%]), and total cholesterol (–49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04233918.
Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study
Authors: William K. Kelly, Daniel C. Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J. Ward, Andrew J. Armstrong, David Pook, Miso Kim, Tanya B. Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G. Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M. Smith, Jamie N. Connarn, Hweixian L. Penny, Julia Stieglmaier, Leonard J. Appleman
Journal: Cancer Discovery (2023)

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development.
Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation
Authors: Liza Afzali‐Hashemi, Elisabeth Dovern, Koen P. A. Baas, Anouk Schrantee, John C. Wood, Aart J. Nederveen, Erfan Nur, Bart J. Biemond
Journal: American Journal of Hematology (2023)

Abstract Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity‐matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased ( p &lt; .01), while GM and WM CVR increased ( p &lt; .01) compared with the baseline measures. OEF and CMRO 2 also increased towards levels in healthy controls ( p &lt; .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis ( p &lt; .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow‐up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.
Antigens localized to B‐cell follicles are protected from proteases: Implications for allergy and allergen immunotherapy
Authors: Danielle Della Libera, Sara Fortier, Joshua F. E. Koenig
Journal: Allergy (2023)

JFEK receives funding from ALK Abello A/S. DDL and SF report no conflicts of interest. No new data was presented in this manuscript.
Decolonization Strategies to Prevent Staphylococcal Infections
Authors: Thomas R. Talbot
Journal: JAMA (2023)

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Specialty Palliative Care for Adolescents and Young Adults With Cancer—Developmental Considerations and an Agenda for Future Research
Authors: Ursula M. Sansom-Daly
Journal: JAMA Network Open (2023)

Sumit Gupta, MD, PhD; Qing Li, MMath; Alisha Kassam, MD, MPH; Adam Rapoport, MD, MHSc; Kimberley Widger, RN, PhD; Karine Chalifour, BSW, BA; Nancy N. Baxter, MD, PhD; Paul C. Nathan, MD, MSc; Natalie G. Coburn, MD, MPH; Rinku Sutradhar, PhD